The insulin and IGF-I receptors are transmembrane tyrosine kinases that are the products of separate genes. In normal physiological states, the insulin receptor mediates the metabolic functions of insulin whereas the IGF-I receptor mediates the effects of IGF-I on growth and development as well as differentiated functions on various tissues. To investigate the regulation and function of the IGF-I receptor we have characterized the IGF-I receptor promoter and have performed studies using site directed mutagenesis to determine the structure/function relationships of various regions of the beta subunit of the receptor. A. The proximal promoter element of the IGF-I receptor lies about 400-500 bp 5' of the single start site for transcription and has no classic TATA or CAAT elements. The transcription start is encompassed by an initiator (INR) sequence. Both the 5' flanking and the long (about 1Kb) 5' untranslated region are GC-rich and contain at least 10 potential binding sites for the transcription factors SP1 and for Wilms' tumor gene product (WT1). We have shown that SP1 enhances promoter activity whereas WT1 inhibits. These studies are important in view of the potential role of the IGF-I receptor in human cancers. B. Our studies have shown that a mutation of the ATP-binding site in the tyrosine kinase domain i.e., replacing the essential lysine residue with either arginine or alanine, prevents autophosphorylation of the beta subunit of the IGF-I receptor and blocks all of the post-receptor events studied, including IGF-I-induced thymidine incorporation, Phosphatidylinositol 3' kinase activity and c-jun/c-fos gene expression. This studies should shed light on the physiological role(s) of the IGF-I receptor in health and disease.